Summary Despite recent advances in tissue engineering and regenerative medicine, heart failure (HF) continues to be the leading cause of death in the U.S., and the rest of the western world. Therefore, our long-term goal is the development of new, minimally invasive tissue-engineered therapies for the treatment of ischemic and nonischemic cardiomyopathy. While cell therapies have been extensively studied for the treatment of MI and HF, meta-analyses of initial cell therapy trials suggest only a modest effect on cardiac function. More recently acellular biomaterials have shown great promise in providing similar or greater functional benefit without the complications associated with cell delivery. Injectable biomaterials that stimulate endogenous repair are an attractive alternative since potential therapies could still be delivered minimally invasively via catheter, yet could be off the shelf and have significantly reduced costs compared to cell products. The PI's lab developed the first cardiac specific injectable hydrogel, which is derived from decellularized porcine myocardial extracellular matrix (ECM) and is deliverable via a transendocardial injection catheter. This material is liquid at room temperature and forms a porous and fibrous scaffold upon injection, which we have shown promotes endogenous cell infiltration and cardiac repair in subacute MI models (injection 1-2 weeks post-MI). This initial work lead to the recent initiation of a clinical trial in post-MI patients. In pre-clinical studies, we showed that injection of the material alone post-MI results in decreased borderzone cardiomyocyte (CM) apoptosis, activation of potential endogenous progenitor cells, a pro-remodeling vs. pro-inflammatory environment, increased neovascularization, reduced fibrosis, a shift in CM metabolism, and increased cardiac muscle, yielding significant improvements in both regional and global cardiac function. Under our previous R01, we were successful in beginning to decipher mechanism of action of this material as well as push forward with translation into patients. In this renewal, we will continue to pursue both basic and translation research goals. We propose to continue to better understand the mechanism of action of the material in the context of subacute MI, specifically answering the remaining question of how the hydrogel increases cardiac muscle. Given the strong need for therapies for acute MI, ischemic HF, and nonischemic HF, we are also proposing studies to enable translation of this material into other patient populations. We hypothesize that the myocardial matrix hydrogel, which contains cardiac specific cues, results in the generation of new cardiac muscle in the context of MI, and that the material can be delivered alone to improve cardiac function in acute MI, as well as ischemic and nonischemic HF.